Heart failure (“HF”) is a major and growing public health problem. In the United States, for example, approximately 5 million patients have HF and over 550,000 patients are diagnosed with HF for the first time each year. (American Heart Association, Heart Disease and Stroke Statistics: 2008 Update, Dallas, Tex., American Heart Association (2008)). Similarly, statistics show that in the U.S. HF is the primary reason for 12 to 15 million office visits and 6.5 million hospitalization days each year. From 1990 to 1999, the annual number of hospitalizations has increased from approximately 810,000 to over 1 million in which HF is the primary diagnosis, and from 2.4 to 3.6 million in which HF is a primary or secondary diagnosis. In 2001, nearly 53,000 patients died of HF as a primary cause. HF is primarily a condition of the elderly, and thus the widely recognized “aging of the population” also contributes to the increasing incidence of HF. The incidence of HF is approaching 10 per 1000 in the population after age 65. In the US alone, the total estimated direct and indirect costs for HF in 2005 were approximately $27.9 billion and approximately $2.9 billion annually is spent on drugs for the treatment of HF. (Id.).
Heart Failure is characterized by a loss in the heart's ability to pump as much blood as the body needs. Failure does not mean that the heart has stopped pumping but that it is failing to pump blood as effectively as it should.
The New York Heart Association (“NYHA”) and the American Association of Cardiology/American Heart Association (“ACC/AHA”) have both established functional classes of HF to gauge the progression of the disease. The NYHA classification scheme has four classes of disease state: Class 1 is asymptomatic at any level of exertion; Class 2 is symptomatic at heavy exertion; and Classes III and IV are symptomatic at light and no exertion, respectively. The ACC/AHA also has a four stage scheme: Stage A is asymptomatic but is at risk for developing HF; Stage B has evidence of cardiac dysfunction without symptoms; Stage C has evidence of cardiac dysfunction with symptoms; and Stage D has symptoms of HF despite maximal therapy.
HF is appreciated in the medical community as a complex disease. It may be caused by the occurrence of a triggering event such as a myocardial infarction (heart attack) or be secondary to other causes such as hypertension, diabetes or cardiac malformations such as valvular disease. Myocardial infarction or other causes of HF result in an initial decline in the pumping capacity of the heart, for example by damaging the heart muscle. This decline in pumping capacity may not be immediately noticeable due to the activation of one or more compensatory mechanisms. However, the progression of HF has been found to be independent of the patient's hemodynamic status. Therefore, the damaging changes caused by the disease are present and ongoing even while the patient remains asymptomatic. In fact, the compensatory mechanisms which maintain normal cardiovascular function during the early phases of HF may actually contribute to progression of the disease in the long run, such as by exerting deleterious effects on the heart and its capacity to maintain a sufficient level of blood flow in the circulation, for example.
Presently, the most (or at least one of the most) useful diagnostic tests in the evaluation of patients with HF is the comprehensive 2-dimensional echocardiogram coupled with Doppler flow studies to determine whether abnormalities of myocardium, heart valves, or pericardium are present and which chambers of the heart are involved. These tests aim to answer three fundamental questions: 1) is the left ventricular ejection fraction (“LVEF”) preserved or reduced, 2) is the structure of the left ventricle (“LV”) normal or abnormal, and 3) are there other structural abnormalities such as valvular, pericardial, or right ventricular abnormalities which may account for the clinical presentation(s). Answers to these questions may be quantified with a numerical estimate of ejection fraction (“EF”), measurement of ventricular dimensions and/or volumes, measurement of wall thickness, and/or evaluation of chamber geometry and regional wall motion. Right ventricular size and systolic performance may be assessed, atrial size may be determined semi quantitatively, and left atrial dimensions and/or volumes may also be measured.
Noninvasive hemodynamic data acquired at the time of echocardiography may also be correlated with other diagnostic information (described above) for patients with preserved or reduced EF. Combined quantification of the mitral valve inflow pattern, pulmonary venous inflow pattern, and mitral annular velocity provides data about characteristics of LV filling and left atrial pressure. Evaluation of the tricuspid valve regurgitant gradient coupled with measurement of inferior vena caval dimension and its response during respiration provides an estimate of systolic pulmonary artery pressure and central venous pressure.
Stroke volume may also be determined with combined dimension measurement and pulsed Doppler in the LV outflow tract. However, abnormalities can be present in any of these parameters in the absence of HF. No one of these necessarily correlates specifically with HF; however, a totally normal filling pattern argues against clinical HF.
From a clinical perspective, the disease is clinically asymptomatic in the compensatory and early decompensatory phases, e.g., completely asymptomatic in stage A and having structural heart disease but no signs and symptoms of HF in stage B (as explained in the above described ACC/AHA practice guidelines). Outward signs of the disease (such as shortness of breath) do not appear until well into the decompensatory phase (i.e., stages C and D according to the ACC/AHA guidelines). Current diagnosis is based on the outward symptoms of patients in stages C and D.
Because individuals at risk of developing HF are generally free of clinical HF symptoms until the later decompensatory stages of HF, the current diagnostic tests are not ideal for early assessment of patients at risk of HF. Further, there are no known, established biochemical markers for the reliable pre-symptomatic assessment of HF. In general, by the time a HF diagnosis is established, HF is already well underway.
At least in-part due to late diagnosis, 50% of patients with HF die within two years of diagnosis. The 5-year survival rate is less than 30%. Furthermore, patients with heart failure typically receive a standard treatment including drugs which interact with specific mechanisms involved in heart failure. There are no diagnostic tests that reflect those specific mechanisms reliably and help the physician to choose the right drug (and dose) for the right patient (e.g., ACE inhibitor, AT II, β-blockers, etc).
As indicated by the above, there exists a need for an improvement in the early assessment and diagnosis of individuals at risk for HF. Thus a marker useful in assessing individuals at risk for HF which, on its own or in combination with other diagnostics evaluations, has a high positive predictive value for HF is of high clinical and practical value. Additionally, a marker (or combination of markers) for aiding in the assessment of a patient with HF is also of value for further technical progress in this clinically important area.